There is evidence that the abnormalities in the reproductive and other neuroendocrine axes in women with hypothalamic amenorrhea (HA) are related to negative energy balance. Leptin levels, which signal the amount of energy stored in adipose tissue to the central nervous system, are low in women with HA. Leptin replacement in leptin-deficient animals and humans results in normalization of reproductive and other neuroendocrine defects in these models. Thus, leptin may serve as the critical link between the sufficiency of energy stores and the integrity of the hypothalamic-pituitary-gonadal axis (HPG). We have demonstrated in a recently completed pilot study that leptin replacement to correct the relative leptin deficiency in women with HA resulted in follicular growth and ovulation, and significantly increased GnRH pulse frequency, estradiol, thyroid hormone, IGF levels, and bone formation markers, suggesting that low leptin levels may contribute to the etiology of the amenorrhea and hormone abnormalities in HA. The results of this pilot study established the "proof-of-concept" that leptin replacement may be a potential treatment for this condition, but further larger, randomized studies are warranted to confirm and extend these findings and to establish the safety and efficacy of leptin treatment for HA. The goal of this proposal is to plan a larger Phase III multi-center, randomized, controlled trial (RCT) of leptin treatment in women with HA. Results of this clinical trial would have significant therapeutic implications for the treatment of HA, since currently available treatment options (i.e., estrogen) have side effects, are not well accepted by some patients, and have suboptimal effectiveness for complications such as osteoporosis. Given that HA accounts for over 30% of amenorrhea in reproductive-aged women and since prolonged amenorrhea can have significant deleterious effects on fertility and bone health, a Phase III RCT of leptin treatment for HA would have considerable clinical impact from a public health perspective. Support is needed to finalize key study design issues, establish collaborative arrangements for a multi-center study, develop an infrastructure for conducting a RCT, and plan subject recruitment strategies.